PROJECT SUMMARY In spite of progress in treatment and promising new drugs multiple sclerosis (MS) continues to be a chronic progressive disease with a high impact on the quality of life of those affected, their families, and society. Further, MS incidence is increasing among US Blacks and among women of all races in several regions in the world. These rapid increases cannot be explained by genetic factors, and strongly suggest that environmental factors, possibly modifiable, are contributing to determine MS risk. Vitamin D is likely to be one of these factors, but questions remain on the role of vitamin D in MS particularly among blacks. Ten years ago, we published a landmark paper reporting that young healthy non-Hispanic white adults with higher serum levels of 25- hydroxyvitamin D (25(OH)D) had a 62% lower risk of developing MS than those with lower levels. This finding, which has been later confirmed in multiple studies, has major public health implications because it supports the notion that the ongoing increase in MS incidence could be halted or reversed by increasing vitamin D levels. An important limitation, however, is that this inverse association between vitamin D and MS risk cannot be generalized to blacks. Further, it remains unclear whether vitamin D levels important only during childhood and adolescence or also during adult life, and whether there are differences between men and women in the vitamin D levels needed to prevent MS. Answering these questions is critical to be able to translate the research findings into sound and effective public health interventions. The proposed study relies on the unique data and blood samples collected from over 10 million individuals during their active duty within the US military and over 60 million serum samples stored in the Department of Defense Serum Repository. The availability of multiple blood samples from each individual prior to MS onset allows an accurate estimate of long term average 25(OH)D levels, and the diverse composition of the study population will allow for the first time to obtain accurate estimates of the relation between vitamin D and MS risk among US blacks, to determine whether the relation between 25(OH)D and MS risk is modified by age or gender, and to explore gene-environment interactions that have potentially important public health implications.